DE2142832A1 - Wormers, 5 aminoimidazoles, their salts with acids and processes for their preparation - Google Patents

Description

¹¹ wormers, 5-aminoimidazoles, their salts with yours and processes for their production "

Priority: August 27, 1970, Great Britain, Mr. '4-1 260/70

The subject of the invention are vermicelli, -which a 5-ainino · - imidazole of the general formula I.

NlL

NH

(D

or de.'jfjen iilautomeres, in which R ^ a non-substituted aryli'otr'o ο ei er hetoroeycliachen E.er.; t and .R ₂ a hydrogen atom, a üarboi ^ -niiü-, an optionally substituted phenyl or Carbor.:..'.j_roü:;[;orgriippe means, or its salt with a ijüuro, hydrate or hydrated salt as an active ingredient as well as customary excipients, '/ diluents and / or auxiliaries.

209810/1895

BAD OfHQlNAL

Specific examples of the radicals 1L are the phenyl, li & phthyl, Thiazolyl, puryl, thionyl, pyridyl and pyrimidinyl groups; the pienyl group is "preferred" that is suitable as the radical Rp Carboxylic acid ester group has the general formula Ia

-G ¹ OOR ₃ (Ia)

in the R, an optionally substituted allyl, aralkyl or aryl radical with up to 12 carbon atoms means <> l> ie loading. Preferred radicals Rp are the phenyl group and radicals of the general Formula Ia, in which R- is an alkyl radical with an even number of carbon atoms in the main chain. Particularly preferred Dewormers contain 5 ~ aminoimidazoles of the general Formula I, the radical Ep of which is an ethoxycarbonyl group »

The compounds of general formula I are used in veterinary medicine, in particular against hematodes. They earth in the form of solutions in pharmacologically acceptable solvents such as water, or f as tablets or capsules in the Han brought v / del. They can also be added to animal feed.

A preferred worming agent according to the invention contains at least a 5-aminoimidazole dissolved or suspended in water general formula I. The solution or suspension can also other active ingredients and / or common ingredients, such as excipients, Contain thickeners, flavorings or preservatives.

If the compounds of the general formula I are administered in a form mixed with the feed, premixes can first be used of the 5-aminoimidazoles of the general formula 1 with v / pus

"209810/189 5 '

SAD ORlGtNAt

2H2832

Waxing agents such as calcium curbonate, bran or flour are made _c

The compounds of general formula I are preferred to animals administered orally. The doses are about 50 to 1000 mg a compound of the general formula I per kg of body weight. In sheep, in general, most parasites are killed by 150 mg / kg, while in chickens 500 mg / kg is required are. . "Doses of 100 to 700 mg / kg are therefore preferred. Most 5-aminoimidazoles in this range have the general formula I a high effectiveness against bematodes Sheep and cattle and against Ascaridia galli in chickens.

! The anthelmintic effectiveness of the compounds of the general Formol I is surprising because known compounds with similar. Structure do not have this effectiveness; see the British Patent documents 683 523, 683 593 and 683 594 as well as Bader et al., J. Chem. Soc. (1950), pages 2772 to 2784. The in den Imidazoles described above were obtained as intermediates in the production of purines and show no biological activity. The by Bader et al. described Imidazoles were created in the wake of the search for new drugs produced, but also have at most a marginal biological effectiveness.

Some 5-AminoimidaKols of the general formula I are new compounds. The invention thus relates to 5-aminoimidazoles of the general formula II

209810/1895 BAD ORlGlNAt

II NH

(II)

or their tautomers, in which R. reads a heterocyclic mid Rp- one hydrogen atom, one carbonamide-, one optionally substituted phenyl or a carboxylic acid ester group with 1 to Means 12 carbon atoms in the alcohol residue, as well as their salts with acids, hydrates and hydrated salts *

The preferred radicals R, are the thienyl, thiazolyl, furyl, pyridyl or pyrimidinyl group. The radical R ₁ -: preferably has a hydrogen atom, a carbonamide or a phenyl group or a carboxylic acid ester group of the general formula 11a

-COOR ₆ (Ha)

in Rg an optionally by a halogen atom or a Alkoxy, aralkoxy or aryloxy substituted ethyl, isopropyl, Butyl, hexyl or benzyl group or optionally one means substituted amino group.

Certain 5-aminoimidazoles of general formula II are Intermediate products for the production of active pharmaceutical ingredients, anti-inflammatory and cytostatic activity against viruses.

The invention also relates to a method for producing the 5-Aminoimidazole of the general formula II and its salts with acids, which is characterized in that according to the usual Methods a nitrile of the general formula III

R ₅ - CH - NH ₂ (III)

CN
20981 0/1895

in which R ₁ - has the representative meaning, with an acid addition salt of a thioether of the general formula IV

I? _ S - C = NH (IV)

in the R. has the above meaning and in the R ₇ a

Alkyl, aralkyl or aryl radical, brings about the reaction, and optionally sets the base free from the salt obtained or from this by reacting it with an inorganic or

organic acid produces a salt.

The inventive process is an analogy process for the UK in the "Patents 683 523, 683 593 and methods described 683 59 ² ^.

In the process of the invention, preference is given to using acid addition salts of thioethers of the general formula IV which have an ethyl or benzyl group _{as radicals R 7.}

The process of the invention is generally carried out in the presence carried out an inert solvent. Examples of suitable Solvents are halogenated hydrocarbons such as chloroform, -Methylene dichloride or methylene dibromide, alcohols such as methanol, Ethanol or hexanol, ether, v / ie tetrahydrofuran, and aromatic

see hydrocarbons like benzene or toluene. To be favoured Chlorinated hydrocarbons, especially chloroform,

The reaction is carried out at temperatures from 0 to 150 C, preferably from 50 to 100 ⁰ C is performed. The reaction temperature is frequently set by using a solvent which boils in the desired range, v / ie chloroform or tetrahydrofuran.

209B10 / 1895

~ 6

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The salts with acids are derived from hydrochloric acid and hydrogen bromide acid, sulfuric acid, nitric acid, formic acid, acetic acid, Tartaric acid, citric acid, ascorbic acid, shark acid and. Malic acid a "b.

Certain benzyl thioethers of the general formula IV are new compounds. These compounds can be obtained by reacting benzyl mercaptan with an ITitrile of the general formula V _;

f R ₄ CN (V)

in which R. has the above meaning, produce in the presence of acids. Ethers such as diethyl ether or tetrahydrofuran can be used as solvents. Dietary anhydrous dietary ether is preferred. It is generally carried out below room temperature, preferably below 10 ° C., for example at ⁰ ° C.

The 3-thienyl form used in the process according to the invention Iminobenzylthioether hydrochloride is produced as follows :

Anhydrous hydrogen chloride is slowly passed into a ^{mixture, cooled to 0} ° C., of 11.9 g (0.109 mol) 3-cyanthiophene, 20.8 g (0.167 mol) benzyl mercaptan and 100 ml anhydrous dioxane over the course of 3 hours with exclusion of water. The mixture is then left to stand for 3 days at room temperature. Then 500 ml of anhydrous dietary ether are added. Crystals separate out, which are filtered off and washed well with dietary ether. 26.8 g of 3-thionyl ~ are obtained

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154 Ms 1 ": ° C;

Yield 90 ^ of theory.

The hydrochlorides of 2-thienylformimnobenzylthioether, 4-ihiazolyiformiminobenzylthioether, 2-purylformiminobenzylthioether, 3-pyridylforminino-isylthioether, 2-pyrimldinylformiminobenzylthioether \ mma-2-formiminobenzylthioether are prepared in an analogous manner.

The examples illustrate the invention.

example 1

yl-2- (3. '-t hienyl) -inido, zol

26.8 g (0.1 Hol) of 3-thienylformiminobenzylthioether hydrochloride are refluxed for 1 hour in 200 ml of chloroform with 25 g (0.2 mol) of ethyl aminocyanoacetate. The mixture is then left to stand for 8 hours and then 250 ml of anhydrous diethyl ether are added. Yield 25.9 g (95 '/ o of theory), 5-amino ~ 4-ethoxycarbonyl-2- (3'-thienyl) -iraidasol hydrochloride. ITach recrystallization from ethanol, the compound melts at 172-173 ⁰ C. By treating with aqueous Natriumcarbonatlösung.v / ith the base of Pp. 224-225 ° G set in freedom.

-2 09810/1895 SAO

Examples 2 to 27

According to Example 1, the "compounds listed in Table I of the general formula II produced:

4th Table I. Marg Pp ₀ , ■ - - 220 ⁰ C - at 0 Hydro -208 free base game 2-thiazolyl chloride 4-thiazolyl Ethoxycarbonyl 214-215 2 2-thienyl Ethoxycarbonyl 218 - • 3 3-thienyl Ethoxycarbonyl 207 - - 145 4th 2-furyl Ethoxycarbonyl - 141 224-225 5 3-pyridyl Ethoxycarbonyl '' '208-209 6th Phenyl Ethoxycarbonyl 222-224 7th 3-thienyl H 144 - 8th 3-thienyl H 140 - 9 2-thienyl Phenyl 183 10 Phenyl • phenyl 187 11 Phenyl. Methoxycarbonyl. 200-202 12th Phenyl i-propoxycarbonyl 203-204 13th Phenyl n-propoxycarbonyl 211-213 14th Phenyl η-butoxycarbonyl 208-209 15th Phenyl t-eutoxycarbonyl 222-224 16 Phenyl i-butoxycarbonyl 239-241 17th n-hexyloxycarbonyl 188.5 18th Phenyl 189.5 Phenyl n-dodecyloxycarbonyl - 128 139-141 19th Phenyl Benzyloxycarbonyl 223-225 20th Phenyl CONH ₂ 300 21st Phenyl β-Chiorethoxycarbonyl 173-174 22nd ß-methoxyethoxycarbo- -126 - 23 Phenyl nyl ■■> · ■ ': ■' - ^; ■ 2-pyrimidinyl ■ ß-P-hen oxyäthoxy carbonyl, 265 24 3-thifenyl " Ethoxycarbonyl 265 25th 3-thienyl :, Benzyloxycarbonyl '240 ~ 243 " 26th ..> irr-Pro, p.oxycarbonyl. =>; -216 -218, 27

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- 9 - Examples 28 to 30

According to Example 1, the compounds listed in Table II are of the general formula I prepared analogously to Example 1.

R ₁ Table II Hydro
chloride ⁰ C
free base at
game Phenyl
Phenyl
2-naphthyl R ₂ ■ 228
271 236 - 237 28
29
30th Ethoxycarb onyl
Phenyl
Ethoxycarbonyl

Examples 31 through 33 illustrate the preparation and use of vermicelli compositions of the invention.

Example 31

100 g of 5-amino-4-ethoxycarbonyl-2-phenylimidazole hydrochloride
suspended in 750 ml of water containing 5 g of gum arabic. 50 ml of the suspension obtained are by means of a
Tube administered to a sheep weighing 50 kg. The animal is then given 50 ml of water.

Example32

The compounds from Example 2 to 30 are processed according to Example 31 to form wormer compositions. When these agents are administered to sheep or sheep at a dose of 150 mg / kg, a marked reduction in worm infestation is achieved

209810/1895

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· "IU ■■

Example 33

10 g of 5-amino-4-phenyl-3-thienylimidazole are added to 200 g Chicken feed mixed. After ingestion of about 500 mg active ingredient / kg corresponding amount of feed is given to the chickens • A 90 percent reduction in Ascaridia galli infestation was noted.

2Ö9810 / 1895

Claims (2)

Patent claims: 1. Antwormers containing a 5-Aminoiraidazole of the general Formula I τ, K ₂ ß _E (I) ^R l or its tautomer, in the R., a non-substituted one Aryl radical or het ^ r cyclic radical and Rp is a hydrogen atom, denotes a carbonamide, an optionally substituted phenyl or carboxylic acid ester group, or its Salt with an acid, hydrate or hydrated salt as Active ingredient and customary carriers, diluents and / or auxiliaries. 2. wormer according to claim 1, characterized in that there is at least one 5-alainoimidazole of the general formula I. contains, in which the radical R ^ is a phenyl, naphthyl, Thiazolyl, thienyl, furyl, pyridyl or pyrimidinyl group, preferably a phenyl group, and the remainder Rp means an ethoxycarb onyl group. ί 3 * 5-aminoimidazoles of the general formula II (II) or their tantomers _t in öer R ^ a heterocyclic radical 209810/1895 and Rj- one hydrogen atom, one carbonamide, one optionally substituted phenyl or carboxylic acid ester group with 1 to 12 carbon atoms in the alcohol radical means, as well as their salts with acids, hydrates and hydrated salts 4. Compounds according to claim 5, characterized in that R, a thienyl, thiazolyl, furyl, pyridyl or pyrimidinyl group and R ₁ - a hydrogen atom, an Oarbonamid- ι or a phenyl group or a carboxylic acid ester group of the _: general formula ^T Ta -COOR ₆ "· (Ha); means,
/ in which Rg denotes an ethyl, isopropyl, butyl, hexyl or benzyl group which is optionally substituted by an halogen atom or an alkoxy, aralkoxy or aryloxy group or an optionally substituted amino group. 5. Compounds according to claim 4-j, characterized in that R ₁ - is an ethoxycarbonyl group. 6. A process for the preparation of the compounds according to claim 3, characterized in that one according to customary methods Uitrile of the general formula III R ₅ -CH- NH _{2 (III)} CN in which R - has the meaning given in claim 3, with an acid addition salt of a thioether of the general Formula IV 2 0 9 8 10/1895 S - G - NH / -γ- (τ \ in which R, which has the meaning given in claim 3 and R _{7 is} an alkyl, aralkyl or aryl radical ", brings about the reaction and optionally liberates the base from the salt obtained or from this by reaction with an inorganic or organic acid makes a salt. Process according to Claim 6, characterized in that an acid addition salt of a thioether of the general formula IV in which R _{7 is} a benzyl group is used. 2 0 9 810/1895